BACKGROUND AND OBJECTIVES: Intrathecal
sufentanil provides analgesia comparable to epidural local anesthetics for labor
pain. Both techniques decrease some parameters of neuroendocrine response to
labor pain and both may mitigate reflex oxytocin release in animals. This study
aimed to compare the effect of both techniques on cortisol (CPC) and oxytocin
(OPC) plasma concentrations in labor patients.METHODS: Participated in this randomized covered study 30 healthy parturients
in spontaneous labor with 4-7 cm cervical dilatation. Group S patients received
intrathecal sufentanil (10 mg) and group B received
epidural 0.25% bupivacaine. Analgesia was assessed by a visual analogue scale
and blood oxytocin and cortisol samples were collected before, 30 and 60 minutes
after drug administration. Plasma cortisol and oxytocin concentrations were
determined by radioimmunoassay.RESULTS: Group S analgesia was more intense at 30 minutes. OPC and CPC
before analgesia were similar for both groups. Group S showed a significant
decrease in OPC at 60 minutes and in CPC at 30 and 60 minutes (p<0.05), while
for Group B such values remained stable throughout the study.CONCLUSIONS: In the conditions of this study, epidural bupivacaine analgesia
was associated to stable plasma cortisol and oxytocin concentrations. Conversely,
intrathecal sufentanil promoted a more intense analgesia and decreased OPC and
CPC.

Labor induces a neuroendocrine and metabolic
response very similar to surgical trauma. It increases the levels of catecholamine
1, cortisol and ACTH 2, corticotrophin (CFG) releasing
hormones and b-endorphins 3. Induced acute stress in pregnant
monkeys decreased uterus-placental flow leading, as a consequence, to fetal
hypoxia, hypotension and bradycardia 4. Exacerbated acute stress
may also cause lactogenesis delay and transient fetal acidosis, which has a
correlation with maternal cortisol plasma concentrations 5,6.

So, cortisol plasma concentrations may be used
as a measure of such response. Oxytocin effect and importance during labor are
well established. Oxytocin is also involved in lactation 7 and stress
response8.

Labor analgesia with epidural local anesthetics
allows for pain control with a consequent decrease in cortisol plasma levels,
however without changing uterine contractility 9. Nevertheless, the
influence of such technique in oxytocin plasma concentrations remains controversial
10,11. The combined spinal-epidural technique has made easier the
use of epidural opioids. Intrathecal opioids produce intense analgesia with
fast onset and without motor block. Animal studies have shown that opioids inhibit
oxytocin release in the hypothalamohypophyseal axle and, in humans, intravenous
morphine may inhibit labor 12,13.The effects of labor analgesia with
intrathecal opioids on cortisol and oxytocin plasma concentrations has not been
reported to date.

This study aimed to evaluate and compare the
effects of epidural analgesia with 0.25% bupivacaine and with intrathecal sufentanil
as to cortisol and oxytocin concentrations in pregnant women with intense labor
pain during the active phase of the first labor stage.

METHODS

This prospective, randomized and blind study
was performed in Hospital das Clinicas, Ribeirão Preto and Maternidade
MATER after the Institutions Research Ethics Committee approval and the
informed consent of patients.

Participated in this study 30 patients aged 18
to 35 years, weighing 50 to 90 kg, physical status ASA I, primiparous or on
second gestation with Cesarean section in the first gestation (functional primiparous),
in the active phase of the first labor stage (cervical dilatation = 4 - 7 cm)
and with the fetus fit in the pelvis. Patients with pre or post term gestation,
presenting signs of acute or chronic fetal suffering and those having received
exogenous oxytocin less than one hour before were excluded from the study. Data
of one patient who quickly evolved to delivery before the end of the study (60
minutes) were excluded and replaced in the sample.

Groups Distribution and Analgesic Technique

When patients asked for analgesia (VAS pain above
7), they were randomly distributed into one of two groups according to the analgesic
technique used. Ten minutes before blockade, all patients received venous hydration
with 300 ml lactated Ringers. Puncture was performed in Group S (n = 15)
with a combined spinal-epidural set with 17G Tuhoy and 27G pencil tip needles
and 2 ml solution with 10 mg sufentanil was intrathecally
injected. Epidural puncture was performed in Group B (n = 15) with 17G Tuhoy
needles and 12 ml of 0.25% bupivacaine were injected. All punctures were performed
at L3-L4 interspace with patients in the sitting position.
Immediately after drug administration and epidural catheter fixation, patients
were placed in the left lateral position with heads up 15º to 20º.
After data collection, 60 minutes after, all patients received epidural bupivacaine
as needed until delivery.

Monitoring and Data Collection

All patients were continuously monitored with
cardioscope, pulse oximetry and respiratory frequency and blood pressure (oscilloscope)
were measured before blockade, at every two minutes for 20 minutes after blockade
and after this, at every 15 minutes. During this sixty-minute study, only brief
and painless gynecologic exams were allowed to determine uterine dilatation.
There has been no spontaneous or provoked membrane rupture during the study.

Pain intensity was evaluated with the help of
a 10 cm linear visual analog pain scale (VAS) where zero was lack of pain and
10 the worst possible or imaginable pain. Evaluations were performed immediately
before the blockade and 30 and 60 minutes after it. The incidence of side-effects,
such as nausea, vomiting, somnolence and hypotension (SBP below 90 mmHg) were
also recorded, as well as the need for specific treatments.

Blood Sample Collection and Hormone Dosage

Venous blood samples (8 ml) were collected with
plastic heparin-containing syringes through a teflon catheter placed in a vein
of the arm opposite to that receiving fluids and drugs at all study moments
(0, 30 and 60 minutes), in a total of 24 ml collected along the experiment.
After collection blood was distributed in two test tubes, one for cortisol dosage
and the other containing EDTA (10 µl/ml blood) for oxytocin dosage.

Test tubes were then temporarily stored in a
styrofoam box at a temperature below 4 ºC, until delivery. After collection,
samples were centrifuged and plasma was stored for three months at 60 ºC until
hormonal dosage.

Oxytocin dosages were obtained by radioimmunoassay
with previous plasma extraction. Intra and inter-assay errors were 2.5% and
14.1% respectively at the level of P0 and ED 50 of the standard curve.

Cortisol dosages were also performed by radioimmunoassay
in duplication without previous extraction 14. Intra and inter-assay
errors were 3.5% and 14% respectively at the level of P0 and ED 50 of the standard
curve.

Statistical Analysis

Hormonal measurements of patients were used as
control and obtained before blockade (paired analysis). To compare groups, initial
hormonal measurement variations were calculated. Data are shown in mean ±
EPM. Hormonal concentrations were analyzed intra and inter groups by Friedman
(paired and non-parametric analysis of variance) and Kruskal-Wallis tests, respectively.
Qualitative variables or proportions were analyzed by Fishers Exact or
Chi-square test. P < 0.05 was considered statistically significant.

RESULTS

There were no statistical differences between
groups as to demographics data (Table
I). All patients were normotensive before blockade (time 0). Baseline heart
and respiratory rates were also similar for both groups, as well as the degree
of parity and cervical dilatation (Table
II). After blockade there has been a transient decrease in systolic blood
pressure in Group B (30 minutes) with pressure levels recovery at 60 minutes.
One group B patient presented with systolic blood pressure of 90 mmHg, which
responded to a fast infusion of 300 ml lactated Ringers. Diastolic blood
pressure and heart rate remained stable for both groups during the observation
period.

All patients had satisfactory analgesia with
AVS below 3 cm, at 30 and 60 minutes. There has been difference between groups
in AVS values at 30 minutes (Figure
1).

Oxytocin plasma concentrations before labor analgesia
were increased and similar for both groups, with means ±
EPM of 9.1 ± 1.1 pg.ml-1 for group
S and 9.8 ± 1.5 pg.ml-1 for group
B. After blockade, there has been a decrease in oxytocin plasma levels in group
S at 30 and 60 minutes, which was statistically significant in paired analysis
with pre-blockade concentrations (p < 0.05). Group B behaved differently
and maintained baseline values throughout the study (Figure
2).

Percentage variation of pre-blockade oxytocin
values was used for intergroup comparisons. There were negative percentage variations
in group S while there were positive percentage variations in group B, with
statistical difference at 60 minutes (p < 0.05). In spite of percentage oxytocin
decreases at moment 30 in group S, there has been no statistical difference
between groups due to major group B variations (Figure
3).

Percentage variations of initial individual concentrations
were used for intergroup comparisons. There were differences in percentage variations
of initial cortisol concentrations between groups S and B at 30 and 60 minutes
(p < 0.05) (Figure
5).

All group S patients presented with mild and
moderate pruritus with no need for naloxone administration. Ten group S patients
(66.6%) presented with mild or moderate somnolence. There has been no pruritus
in group B and two patients (16.6%) presented with somnolence. There has been
no oxygen saturation decrease below 92%. However, two group B patients presented
with transient bradypnea with respiratory rate of 9 ir/min, but with no need
for intervention because both patients were asleep at that time and as soon
as awakened their respiratory rate increased.

DISCUSSION

Although not being blind, this study was homogeneous
as to groups distribution. Hormone values before analgesia were especially
important for this study because they worked as controls in paired analysis
with post-blockade values, thus allowing for an accurate analysis of analgesia-induced
changes in all variables studied.

Obstetric hypotension may be noxious both for
the mother and the fetus (decreases uterine perfusion), and may decrease uterine
activity leading to fetal hypoxia 15. Clinical studies have shown
that both spinal sufentanil and epidural analgesia reduce blood pressure in
a similar manner 16,17.

Our results are different from those studies
because systolic blood pressure (SBP) variations were higher for group B at
30 minutes, as compared to controls (time zero). However, there are no descriptions
in those studies of patients receiving pre-blockade volume expansion, leading
to a higher chance of hypotension, what is different from our method. In our
study, one group B patient had an SBP decrease below 90 mmHg, which responded
to lactated Ringers infusion, thus suggesting that there were more intense
hemodynamic changes in this group.

Two group S patients had a respiratory rate of
9 irpm, but none had SpO2 below 92%. Somnolence after analgesia induction
may be explained by maternal stress and fatigue attenuation. However, a higher
incidence of somnolence in group S (66.6%), as compared to 16.6% in group B,
as well as all group S patients presenting with pruritus, suggest a rostral
spread of the drug. Pharmacokinetic studies of sufentanil in ewes have shown
that intrathecal administration is followed by high drug concentrations in the
cisterna magna after 10 minutes and that CSF concentrations are always higher
than plasma concentrations, confirming CSF rostral spread 18.

Opioid-containing solutions baricity may influence
rostral spread and analgesia efficacy 19 and 5 µg.kg-1
sufentanil is hypobaric at 37 ºC, which favors the cephalic spread if the patient
remains too long in the sitting position during blockade 20. In our
study, time needed for epidural catheters insertion after intrathecal injections
was less than 5 minutes.

Labor analgesia onset with intrathecal sufentanil
is faster than epidural onset with local anesthetics 17. Our study
has reproduced such results with statistical differences in pain intensity up
to 30 minutes after beginning of analgesia.

It is a consensus that cortisol plasma concentrations
progressively increase during gestation, maintaining the circadian rhythm and
reaching the end of gestation with a substantially higher titration as compared
to non-pregnant women 2. When labor begins there is a progressive
cortisol increase with peak plasma concentration soon after birth 21.
Such increase is partially inhibited by epidural labor analgesia with local
anesthetics 9.

Cortisol may influence labor because, in ewes
at the end of gestation, oxytocin receptor messenger RNA expression increased
to prepare myometrium for labor 22. The fact that cortisol decreases
progesterone and increases estrogen production via 17 a-hydroxylase
23 activation and 15-hydroxyprostaglandin dehydrogenase inhibition
24 suggests an important cortisol role in triggering labor. However,
the increase during labor is directly related to emotional stress and pain intensity
and seems to be related to post-partum infection and psychic alterations 25-26.

Our results confirmed high cortisol plasma concentrations
in the active phase of labor, which decreased after analgesia in group B and
was different from group S where it remained constant. This was probably due
to the higher incidence of residual pain in group B.

Several authors tried to correlate pain blockade
with neuroendocrine response attenuation 27. However, in those studies,
it was impossible to rule out the participation of neural blockades, other than
pain. In our study, the marked cortisol release blockade in group S suggests
that pain pathways have an important role in the neuroendocrine response.

There is also the possibility of cephalic opioid
spread with inhibition of corticotropin releasing factor release 28.
So, intrathecal sufentanil in labor analgesia blocks cortisol release by the
hipothalamohypophysial axle probably by blocking pain, suggesting an important
participation of pain pathways in neuroendocrine stress response.

Studies involving oxytocin labor dosages have
some methodological difficulties. Due to its fast metabolization via oxytocinase,
peripheral venous blood concentration is a fraction of that found in the internal
jugular vein. Oxytocin pulses release in blood flow is another factor which
may influence oxytocin peripheral plasma levels 29. So, we did not
allow obstetric maneuvers and membrane rupture during the 60 minutes of study,
and blood samples were collected always during uterine peak contraction intensity.
Another factor impairing results interpretation is the wide variation in oxytocin
plasma levels among labor patients. So, we used the dose immediately before
analgesia as the control for each patient, according to methods used in other
studies 30.

It was to be expected that intrathecal sufentanil
would not interfere with Fergusons reflex for acting specifically on the
dorsal spine of the spinal cord, preferably modulating pain pathways without
affecting perineal distension sensitivity pathways. However, our data show that
plasma oxytocin was significantly reduced after intrathecal sufentanil administration
as compared to control, what was not seen with the use of epidural local anesthetics.
This oxytocin decrease shows the interference of the intrathecal administration
of a potent and fast-acting µ-specific opioid on Fergusons reflex,
which could directly influence labor evolution.

Two hypotheses may explain plasma oxytocin decrease
in group S and not in group B. The first is that Fergusons reflex has
a strong afference in pain pathways, which would justify the maintenance of
oxytocin plasma concentrations in group B, because patients had adequate analgesia
but not so deep as group S. In this case, the action of opioids and local anesthetics
on oxytocin would preferably be in the spinal cord. The second hypothesis is
that intrathecal sufentanil would have a rostral spread reaching the hypothalamohypophyseal
axle and inhibiting oxytocin release by the posterior hypophysis lobe at the
central level.

Oxytocin endogenous secretion mechanisms are
highly complex and were not yet fully explained. Opioid action on hypothalamohypophyseal
axle (HHA) inhibiting oxytocin release was described in experimental studies
in vitro31 and in vivo in rats 32.

The presence and action of m
and k opioids in the hypothalamohypophyseal axle
has been widely shown, especially in Supra-Optic and Paraventricular Nuclei
33. In Supra-Optic Nuclei magnocellular neurons, the population of
k receptors is larger than of m
receptors and its activation promotes a decrease in electric activity and neuronal
hyperpolarization inhibiting neuro-hypophysis oxytocin release 34.
However, in rats in the end of gestation, a decrease in k
agonists response and an increase in m receptors
activity have been observed 13,35. There are evidences of m
and k receptors populations in the hypophysis posterior
lobe, because intra-cerebral naloxone (m selective
antagonist) promotes oxytocin release 31.

Uterine activity and oxytocin plasma levels in
rats during labor decreased after subcutaneous or intra-cerebral morphine, leading
to a prolonged labor and showing the inhibiting action of m
agonist opioids on central Fergusons reflex 36. Although an
extensive literature on the modulation of opioids in oxytocin release in animals,
few studies were carried out with humans, probably due to methodological and
ethical difficulties in performing such experiments. With the development and
major progresses in intrathecal analgesia with liposoluble opioids in the late
80s, such subject became very important.

Intravenous 5 mg morphine, administered during
the first labor phase, decreases plasma oxytocin in the peripheral circulation,
probably by inhibiting hypothalamohypophyseal axle release 12, establishing
the first correlation between clinical and experimental trials. During the second
labor phase, intravenous morphine was unable to block oxytocin release, probably
due to the higher stimulus intensity and the lower analgesic efficacy of intravenous
morphine during this phase 37. Inhibitory response to labor-induced
oxytocin release, both of k and m
agonists, depends on the number and intensity of sensory afferences 38,
which confirms the possibility of oxytocin release inhibition by opioids being
labor phase-dependent.

The possibility of cephalic sufentanil spread
has been previously discussed. We were unable to show that sufentanil had reached
the supraspinal region, but the high incidence of somnolence and pruritus and
the decrease in respiratory rate in two group S patients suggest the possibility
of rostral spread. The fact of analgesia not changing plasma oxytocin in group
B suggests that other mechanisms, other than pain blockade, are involved in
oxytocin decrease in group S and that sufentanil action site, for decreasing
oxytocin levels, should be supraspinal.

Previous studies on the effect of epidural anesthesia
with local anesthetics on oxytocin plasma levels had different results and conclusions.
Patients receiving epidural analgesia had a decrease in oxytocin plasma levels
after blockade 10, which is different from our results. In that study,
however, analgesia was induced at the end of the second labor phase, when sensory
afference and the consequent oxytocin release are intense and total block with
local anesthetics could show a better effect in oxytocin reflex release, which
is different from our method. Although without group B oxytocin decrease in
our sample, there was also no increase, as it should be expected during natural
labor evolution.

Labor analgesia with intrathecal opioids does
not produce loss of abdominal press and does not relax pelvis muscles.

Such factors could cause rotation dystocia and
prolong labor, which could explain a faster labor evolution with such technique.
In spite of the seemingly labor maintenance, the effects of oxytocin levels
decrease in uterine contractility and labor evolution were not the objective
of this study. Uterine contractility control mechanisms are complex and partially
explained. Other factors, such as decreased catecholamine plasma concentrations
and number of oxytocin receptors in the myometrium may override oxytocin decrease.

Concluding, intrathecal sufentanil decreases
oxytocin plasma concentrations. The possible action mechanism is the release
inhibition of hypothalamohypophysial axle. The confirmation of the action mechanism
and of the influence on uterine contractions needs additional studies with a
specific method.